Genetic Variant CADPS:p.Lys1218Arg (chr3-62445781-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003716.4(CADPS):c.3653A>G(p.Lys1218Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,522,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

CADPS
NM_003716.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.80

Publications

3 publications found

Variant links:

Genes affected

CADPS (HGNC:1426): (calcium dependent secretion activator) This gene encodes a novel neural/endocrine-specific cytosolic and peripheral membrane protein required for the Ca2+-regulated exocytosis of secretory vesicles. The protein acts at a stage in exocytosis that follows ATP-dependent priming, which involves the essential synthesis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Alternative splicing has been observed at this locus and three variants, encoding distinct isoforms, are described. [provided by RefSeq, Aug 2008]

CADPS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08925685).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003716.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CADPS	NM_003716.4	MANE Select	c.3653A>G	p.Lys1218Arg	missense	Exon 27 of 30	NP_003707.2
CADPS	NM_001438347.1		c.3713A>G	p.Lys1238Arg	missense	Exon 28 of 31	NP_001425276.1
CADPS	NM_001438348.1		c.3701A>G	p.Lys1234Arg	missense	Exon 27 of 30	NP_001425277.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CADPS	ENST00000383710.9	TSL:1 MANE Select	c.3653A>G	p.Lys1218Arg	missense	Exon 27 of 30	ENSP00000373215.4	Q9ULU8-1
CADPS	ENST00000612439.4	TSL:1	c.3626A>G	p.Lys1209Arg	missense	Exon 25 of 28	ENSP00000484365.1	F1T0E5
CADPS	ENST00000283269.13	TSL:1	c.3536A>G	p.Lys1179Arg	missense	Exon 25 of 28	ENSP00000283269.9	Q9ULU8-3

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000808

AC:

AN:

173164

AF XY:

0.0000833

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000372

Gnomad ASJ exome

AF:

0.00135

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000562

AC:

AN:

1371060

Hom.:

Cov.:

AF XY:

0.0000529

AC XY:

AN XY:

680688

show subpopulations

African (AFR)

AF:

0.0000362

AC:

AN:

27608

American (AMR)

AF:

0.000237

AC:

AN:

25284

Ashkenazi Jewish (ASJ)

AF:

0.00229

AC:

AN:

21830

East Asian (EAS)

AF:

0.00

AC:

AN:

35360

South Asian (SAS)

AF:

0.00

AC:

AN:

70792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5340

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1078056

Other (OTH)

AF:

0.000142

AC:

AN:

56166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151214

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73750

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41172

American (AMR)

AF:

0.0000659

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67872

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000123

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.014

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.6

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.4

REVEL

Benign

0.15

Sift

Benign

0.087

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.56

MVP

0.48

MPC

0.65

ClinPred

0.17

GERP RS

5.6

Varity_R

0.22

gMVP

0.085

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over